Hydraulic cement compositions with low ph methods, articles and kits

ABSTRACT

A non-aqueous hydraulic cement composition comprises a non-aqueous mixture of (a) β-tricalcium phosphate powder, (b) monocalcium phosphate comprising monocalcium phosphate anhydrous (MCPA), monocalcium phosphate monohydrate (MCPM), or a combination thereof, and (c) non-aqueous water-miscible liquid, wherein a 0.1 g/ml saturated aqueous solution of the monocalcium phosphate has a pH less than 3.0. Methods of producing a hardened cement, hardened cements, kits, and articles of manufacture employ such compositions.

FIELD OF THE INVENTION

The present invention is directed to hydraulic cements, and, more particularly, to non-aqueous hydraulic cement compositions or partly aqueous compositions. The hydraulic cement compositions may be formed into hardened cements by contact with a hydration liquid or vapor. In a specific embodiment, the hydraulic cements are suitable for use as biomaterials for in vivo delivery, for example for bone and tooth-root restoration. The invention is also directed to hardened cements formed from such hydraulic cement compositions and to methods of producing hardened cements. The invention is further directed to kits and articles of manufacture including, inter alia, such hydraulic cement compositions.

BACKGROUND OF THE INVENTION

Self-hardening calcium phosphate cements (CPC) have been used for bone and tooth restoration and for local drug delivery applications. See, for example, Larsson et al, “Use of injectable calcium phosphate cement for fracture fixation: A review,” Clinical Orthopedics and Related Research, 395:23-32 (2002) and Oda et al, “Clinical use of a newly developed calcium phosphate cement (XSB-671D),” Journal of Orthopedic Science, 11(2):167-174 (2006). The cements in powder form are typically mixed with an aqueous solution immediately before application. In the clinical situation, the ability of the surgeon to properly mix the cement powder and hydrating liquid and then place the cement paste in a defect within the prescribed time is a crucial factor in achieving optimum results. Specifically, the dry cement powder material needs to be mixed with an aqueous solution in the surgical setting, i.e., the operating room, transferred to an applicator, typically a syringe, and delivered to the desired location within the setting time. Conventional cements generally have a setting time of about 15-30 minutes. However, the methods used for mixing and transfer of cement for injection in the operating room are technically difficult and pose a risk for non-optimal material performance, e.g., early setting renders materials difficult to inject or causes phase separation, so-called filter pressing. Further, for technical reasons and time constraints, the material is typically mixed with a hydrating liquid in bulk to form a paste and the paste is then transferred to smaller syringes for delivery. In practice, material is often wasted due to an early setting reaction, i.e., the hydrated material sets to a hardened cement prior to delivery to the desired location, or because more material than is needed is mixed. A solution to these problems that includes the possibility to deliver material in smaller quantities in a more controlled manner is thus desired.

The problem of obtaining a proper mix of the powder material and hydrating liquid for optimum clinical results in apatite cements has been addressed in US 2006/0263443, US 2007/0092856, Carey et al, “Premixed rapid-setting calcium phosphate composites for bone repair,” Biomaterials, 26(24):5002-5014 (2005), Takagi et al, “Premixed calcium-phosphate cement pastes,” Journal of Biomedical Materials Research Part B-Applied Biomaterials, 67B(2): 689-696 (2003), Xu et al, “Premixed macroporous calcium phosphate cement scaffold,” Journal of Materials Science-Materials in Medicine, 18(7):1345-1353 (2007), and Xu et al, “Premixed calcium phosphate cements: Synthesis, physical properties, and cell cytotoxicity,” Dental Materials, 23(4):433-441 (2007), wherein premixed pastes are described. In US 2006/0263443, for example, a powder composition for hydroxyapatite is premixed with an organic acid and glycerol to form a paste, which paste may subsequently be injected into a defect. The injected material hardens through the diffusion of body liquids into the biomaterial. The organic acid is added to increase resistance to washout and the end product after setting is apatite, which is known to have a long resorption time in vivo as described above. Also, compositions of β-tricalcium phosphate (β-TCP) and hydrated acid calcium phosphate in glycerin or polyethylene glycol have previously been described in CN 1919357. Han et al, “β-TCP/MCPM-based premixed calcium phosphate cements,” Acta Biomaterialia, doi:10.1016/j.actbio.2009.04.024 (2009) and Aberg et al, “Premixed acidic calcium phosphate cement: characterization of strength and microstructure, Journal of Biomedical Materials Research, 2010, May; 93(2):436-41. However, it is difficult to obtain sufficient shelf life using the described formulations in the prior art, as also noted by Shimada et al, Journal of Research of the National Institute of Standards and Technology “Properties of Injectable Apatite-Forming Premixed Cements,” 115(4): 240 (July-August 2010). Shelf life is also a problem for reactive Brushite forming cements. Tests have been performed using monocalcium phosphate anhydrous (MCPA), where difficulties to achieve a rapid setting time resulted when changing from MCPM (monocalcium phosphate monohydrate) to MCPA.

Thus, there is a continuing need to be able to efficiently prepare, store and safely deliver hydraulic cements, particularly for biomedical applications, i.e., hydraulic cements that overcome the above noted and/or other difficulties of conventional hydraulic cement materials, while optionally optimizing performance properties.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide hydraulic cements, and hardened cements, methods, kits and articles of manufacture based on the hydraulic cements, with an optimized handling and biological response for clinical use.

In one embodiment, the invention is directed to a non-aqueous, hydraulic cement composition, which comprises a non-aqueous mixture of (a) β-tricalcium phosphate powder, (b) mono calcium phosphate anhydrous (MCPA) or monocalcium phosphate monohydrate (MCPM), or a combination thereof, and (c) non-aqueous water-miscible liquid.

In the specific embodiment the MCPA and MCPM powders that in a saturated aqueous solution of the powders have a pH below 3 are used in order to obtain proper hardening.

In another embodiment, the invention is directed to non-aqueous, hydraulic cement composition which comprises a non-aqueous mixture of (a) β-tricalcium phosphate powder (b) mono calcium phosphate anhydrous (MCPA) or monocalcium phosphate monohydrate (MCPM) or a combination thereof, (c) non-aqueous water-miscible liquid and d) porous β-tricalcium phosphate (β-TCP) granules. In most bone applications, it is preferred to have a cement composition that resembles natural bone the most. As such calcium phosphate cement is the preferred cement over other compositions.

To achieve a faster setting time and also allow for hardening of large amounts of injected material, water can be added to the composition. In one embodiment, 1-50 vol % water, more specifically 3-30 vol % water, or more specifically, 15-30% water, based on the volume of water and non-aqueous water miscible liquid, may be employed. Typically, water, if employed, is added shortly prior to use.

The invention is also directed to methods of producing a hardened cement with such compositions, hardened cements produced from such compositions, kits including such compositions, and articles of manufacture including such compositions.

The hydraulic cement compositions according to the invention are advantageous in that they avoid many of the preparation difficulties of conventional hydraulic cement compositions, particularly when used as biomaterials, and may be easily and efficiently delivered to a desired location, without excessive material waste. Additionally, the hydraulic cement compositions according to the invention may be optimized for improved shelf life. These and additional objects and advantages of the present invention will be more fully appreciated in view of the following detailed description.

DETAILED DESCRIPTION

The non-aqueous, hydraulic cement compositions of the present invention are suitable, in one embodiment, for use in biomedical applications. The present description refers to use of the compositions for in vivo applications, for example in bone and tooth repair. It will be appreciated that the present compositions are suitable for other in vivo applications as well as for non-biomaterial applications. The compositions of the invention contain non-hydrated powder and will hydrate upon contact with a hydrating liquid or vapor, typically water, body fluids or other aqueous solution.

In a first embodiment, the non-aqueous, hydraulic cement composition comprises a non-aqueous mixture of (a) β-tricalcium phosphate powder, (b) mono calcium phosphate anhydrous (MCPA) or monocalcium phosphate monohydrate (MCPM) or a combination thereof, and (c) non-aqueous water-miscible liquid. After hardening, the cement will form Brushite (CaHPO₄-2H₂O) in temperature ranges of about 0-20° C. and Monetite (CaHPO₄) in temperature ranges of about 35-100° C. In the range between 20 and 35° C. a mixture of the two phases will form.

The MCPA and MCPM should exhibit a pH of below 3, and in further embodiments a pH of at least 2 in a saturated aqueous solution. In a more specific embodiment, the MCPA and MCPM should exhibit a pH of 2.5-2.8. Measurement of pH can typically be measured using a saturated aqueous solution of the powders (including glycerol), about 0.1 g/mL. The pH of these solutions can then be measured using a standard pH meter. The indicated pH allows a faster setting and more complete chemical reaction during hydration of the cement. Below pH 2, MCPA and MCPM are less soluble in water; however, a lower pH will render cements with faster setting times and are therefore preferable.

In one embodiment, the monocalcium phosphate consists essentially of MCPA, whereby significant amounts of MCPM, i.e., greater than about 25%, or greater than about 10%, or greater than about 5%, based on the weight of the monocalcium phosphate, are excluded. In another embodiment, the monocalcium phosphate consists of MCPA. The MCPA does not contain any crystal water as is the case with mono calcium phosphate monohydrate. This makes the inventive compositions more stable during storage, especially in temperatures below 20° C. (where brushite is formed), since any additional water in the cement formulation will be bound to the formed brushite (CaHPO₄-2H₂O).

Generally aqueous cement compositions mixed with water benefit from smaller particle sizes in the powder composition since this gives faster setting time and stronger cements. However, it has been discovered that premixed cements are affected differently. When too small of particles sizes are used (i.e., mean grain size about 1 micrometer or less), the premixed cements are difficult to inject. For the premixed cements, the setting time is not affected to the same extent since in addition to the non-aqueous liquid dissolution rate, the diffusion rate of water into the cement also controls the setting time. Therefore, smaller particles do not necessarily give faster setting times compared to cements with larger particles. Larger particles make the cement easier to inject than finer particle size powders. While not wishing to be bound by theory, it is believed that there is more glycerol (on average) between each powder grain, resulting in an easier shear of the cement paste and easier injection. In addition, the porosity is important to be able to control since the porosity affects bone ingrowth and the resorption time in vivo, Ginebra et al, “In vivo evaluation of an injectable Macroporous Calcium Phosphate Cement” Journal of Materials Science-Materials in Medicine, 18(2):353-361 (2007). By controlling the MCP particle size it is possible to control the porosity in the cement. In previous cement formulations, additional additives were added in order to obtain the desired porosity. Furthermore, conventional water mixed cements harden without any substantial liquid exchange in vivo since the water present in the cement is enough for the hardening to occur. For the cements in the present invention, a liquid exchange must occur between the non-hydrated liquid in the cement and hydration liquid, i.e., the surrounding body fluid (blood) in vivo use. During this liquid exchange, biological components will be transported into the cement, which are beneficial for faster bone ingrowth and resorption of the cement. This liquid exchange will benefit from larger particle sizes that allow a quicker liquid exchange during hardening through the larger pores, which are formed when the MCPM and/or MCPA dissolves and since there is more glycerol (on average) between each powder grain.

In specific embodiments, at least 75%, at least 80%, at least 85%, or at least 90% of the MCP particles, or, more specifically, the MCPA particles, are of a size about 200-600 μm, more specifically about 400-600 μm. In specific embodiments, the powder to liquid ratio (P/L) is (weight/volume) about 2.5-5.5, more specifically about 3.5-5, to obtain a porous cement upon hardening, allowing for faster bone ingrowth. In further embodiments, the MCP, or specifically, MCPA, particles size is about 0.01-400 μm, more specifically about 0.01-200 μm, and most specifically, about 0.01-100 μm, but larger than about 1 μm, and the P/L is about 2-5, more specifically about 3-4.5, for a cement with higher mechanical strength. In a specific embodiment, the particle size range is wide, about 0.1-600 μm, and the P/L is about 2.5 and 5.5, more specifically about 3.5 and 5, for a cement with some larger pores allowing fast diffusion and that is mechanically strong.

In a further embodiment, the non-aqueous, hydraulic cement composition comprises a non-aqueous mixture of (a) β-tricalcium phosphate powder, (b) mono calcium phosphate anhydrous (MCPA) or monocalcium phosphate monohydrate (MCPM) or a combination thereof, preferably MCPA, (c) non-aqueous water-miscible liquid, and d) porous β-tricalcium phosphate (β-TCP) granules. The porous β-TCP granules modify the resorption rate and bone remodelling of the hardened cement which is formed upon hydration and setting. The granules generally comprise agglomerated powders and the porosity of the granules comprises pores formed between individual powder grains in the agglomerates. In a specific embodiment, the granule size is from about 10 to about 3000 micrometers. In a further embodiment, the granule size is from about 10 to about 1000 micrometers and may be selected to optimize mechanical and/or biological properties of the resulting hardened cement. In a specific embodiment, the granule porosity is at most 80 vol % and the pore size is at most 500 micrometers.

In a specific embodiment, the weight ratio of porous β-TCP granules to additional powder in the non-hydrated powder composition is in a range about 1:3 to about 3:1, or, more specifically, in a range of about 2:1 to about 1:2.

In the first and second embodiments of the invention as described above, any suitable, non-aqueous water-miscible liquid may be employed to form the premixed paste (i.e. the paste that is subsequently injected in vivo). Exemplary liquids include, but are not limited to, glycerol, propylene glycol, poly(propylene glycol), poly(ethylene glycol) and combinations thereof, and related liquid compounds and derivatives, i.e., substances derived from non-aqueous water miscible substances, substitutes, i.e., substances where part of the chemical structure has been substituted with another chemical structure, and the like. Certain alcohols may also be suitable as mixing liquid. In a specific embodiment, the liquid is glycerol.

The powder to non-aqueous water-miscible liquid weight to volume ratio (P/L) may suitably be in a range of from about 0.5 to about 10, more specifically from about 1 to about 7, and more specifically from about 2.5 to about 7, or from about 2.5 to about 5, for better handling and mechanical strength. These ratios are suitable even if two or more liquids are used in combination.

The hydraulic cement compositions of the invention may also include agents that facilitate a fast diffusion of water formed in situ into the paste which is formed by the powder composition and the non-aqueous liquid. In one embodiment, the agent comprises a surfactant, more specifically a non-ionic surfactant, an example of which includes, but is not limited to, a polysorbate. The amount of surfactant may vary from about 0.01 to about 5 weight % of the powder composition, or, more specifically, from about 0.1 to about 1 weight %. See, for example, Shimada et al, “Properties of Injectable Apatite-Forming Premixed Cements”, Journal of Research of the National Institute of Standards and Technology, 115(4):240 (July-August 2010).

The hydraulic cement compositions of the invention may also include one or more porogens to provide a macroporous cement product. A macroporous cement product facilitates fast resorption and tissue in-growth. The porogen may include sugars and other fast-resorbing agents, and non-limiting examples include calcium sulphate, mannitol, poly(a-hydroxy ester) foams, sucrose, NaHCO₃, NaCl and sorbitol. The amount of porogen may suitably be from about 5 to about 30 weight % of the powder composition. The grain size of the porogens are typically in the range of 50 to 600 μm.

The hydraulic cement compositions of the invention may also include one or more non-toxic gelling agents to enhance cohesiveness and washout resistance of the compositions upon delivery. Exemplary gelling agents include, but are not limited to, chitosan, collagen, gum, gelatin, alginate, cellulose, polyacrylic acid (PAA), polyacrylic maleic acid (PAMA), polymethacrylic acid (PMA), neutral polyacrylic and/or polymethacrylic acid and/or polyacrylmaleic acid (e.g. Na-PAA, Na-PMA, Na-PAMA), hydroxypropylmethyl cellulose (HPMC), hydroxymethyl cellulose (HMC), polyvinylpyrrolidone (PVP), and carboxymethyl cellulose (CMC), and combinations thereof. The amount of gelling agent represents suitably from about 0.1 to about 7 weight % of the powder composition, more specifically from about 0.1 to about 2 weight %.

The hydraulic cement compositions are formed into hardened cement materials by contact with a hydrating liquid or vapor. In a specific embodiment, a hydrating liquid is employed. The hydration liquid may be any polar liquid, such as water and other polar protic solvents (e.g. alcohol). The hydrating liquid is suitably water or an aqueous solution. The hydrating liquid can optionally have a pH within the range of 1-9. According to one embodiment; the powder compositions as described in the present invention are premixed with a liquid containing a combination of non-aqueous liquid and water. When used, the water concentration is suitably below 50% (vol/vol), more preferably about 10-40% or about 15-30% (vol/vol), based on both the non-aqueous liquid and water.

The hydraulic cement compositions in the form of a premixed paste may be delivered, for example, to an implant site when used as a biomaterial, using a syringe or spatula. The hydraulic cement compositions may be shaped in vivo, and subsequently be hydrated or be allowed to hydrate in vivo. Optionally, a water-containing liquid can be added to the premixed paste before delivery, for example before applying the material in vivo using a spatula.

The hydraulic cement compositions in the form of a premixed paste can also be packaged in a vacuum package to reduce the amount of air voids in the paste and thus increase the final strength of the hardened material. Air voids reduce the strength of the set material and reduction of air voids is therefore important. The hydraulic cement compositions may be conveniently mixed and packaged under vacuum conditions. Preferably the hydraulic cement compositions are vacuum-mixed (e.g. in a Ross Vacuum Mixer Homogenizer).

In another embodiment of the invention, the hydraulic cement compositions may be provided as a component of a kit or article of manufacture, for example in combination with a separately contained quantity of hydrating liquid or in a double barrel syringe with the reactive components separated in two barrels. In a specific embodiment, a kit comprises several prefilled syringes of the same or of various sizes. Another non-limiting example is a kit with several 2 ml prefilled syringes. Another non-limiting example is a kit with several 1 ml prefilled syringes. Thus, another embodiment of the invention comprises an article of manufacture comprising a hydraulic cement composition in a dispensing container, more specifically a syringe. In another non-limiting example, the cement compositions is provided in a jar, then the cement is preferably applied using a special device, for example, a spatula or a spoon.

The described hydraulic cement compositions are suitably employed as injectable in situ-setting biomaterials or as putties. The compositions can be used as any implant, more specifically as a bone implant, more specifically as dental or orthopedic implant. In a specific embodiment, the hydraulic cement compositions are suitable used as material in cranio maxillofacial defects (CMF), bone void filler, trauma, spinal, endodontic, intervertebral disc replacement and percutaneous vertebroplasty (vertebral compression fracture) applications.

Various embodiments of the invention are illustrated in the following Examples.

Example 1

This example shows the effect of the pH of monocalcium phosphate has on the setting properties of the cement formulation.

Monocalcium phosphate monohydrate and anhydrous from 5 different suppliers were evaluated. When the anhydrous form could not be obtained from the supplier, the MCPM was heated to 120° in order to form MCPA. The particle size of the tested MCPA and MCPM powders was in the range of 10-400 μm. Saturated aqueous solutions of the powders (including glycerol) were prepared (0.1 g/mL). The pH of these solutions was measured using a standard pH meter. The different MCPA and MCPM powders were then used in cement formulations prepared with a powder to liquid ratio of 3.5 g/mL. The cements were evaluated regarding setting time.

Setting Time (ST)

To evaluate setting time of the cements, they were injected in five cylindrical moulds, diameter 6 mm, height 3 mm. At t=0, the filled moulds were immersed in 37° C. phosphate buffered saline solution (PBS, pH 7.4, Sigma), to simulate in vivo conditions. The cement was considered to have set when the sample could support the 453.5 g Gillmore needle with a tip diameter of 1.06 mm without breaking.

The results are set forth in Table 1:

TABLE 1 pH and setting time using various MCPA and MCPM Supplier pH Setting time Scharlau: MCPM 2.8 ~40 min Scharlau: MCPA 2.8 ~40 min Innophos MCPM 3.5 No setting Innophos MCPA 3.5 No setting HiMed, MCPM 3.5 No setting HiMed, MCPA 3.5 No setting Chempur, MCPM 2.7 ~40 min Chempur, MCPA 2.8 ~40 min Strem, MCPM 2.5 ~40 min Strem, MCPA 2.6 ~40 min

The results show the importance of pH of the MCPM or MCPA for the setting of the cement.

Example 2

This example shows that use of MCPA instead of MCPM increases the shelf life of the cement formulation. The shelf life in room temperature of the cement using MCPA was significantly longer than when using MCPM.

Cement Preparation

Two cement formulations were evaluated. Cement 1 consisted of monocalcium phosphate hydrate (Alpha Aesar, containing both MCPM and MCPA) and β-tri calcium phosphate (β-TCP, Sigma) in a molar ratio of 1:1. Anhydrous glycerol was used as mixing liquid. Cement 2 consisted of monocalcium phosphate anhydrous (MCPA) and β-tri calcium phosphate (β-TCP) in a molar ratio of 1:1. Anhydrous glycerol was used as mixing liquid. A powder to liquid ratio (P/L) of 4 (g/ml) was used for both cements. The MCPA was produced by heating the monocalcium phosphate hydrate powder to 110° C. for 24 h. A vacuum mixer was used to mix the cements.

Setting Time (ST)

To evaluate setting time, the cement was injected in four cylindrical moulds, diameter 6 mm, height 3 mm. At t=0, the filled moulds were immersed in 37° C. phosphate buffered saline solution (PBS, pH 7.4, Sigma), to simulate in vivo conditions. The cement was considered to have set when the sample could support the 453.5 g Gillmore needle with a tip diameter of 1.06 mm without breaking.

Compressive Strength (CS)

For CS measurements, the paste was injected into cylindrical moulds and immersed in 50 ml PBS at 37° C. in a sealed beaker. Sample dimensions were diameter 6 mm and height 12 mm. After 24 h, the samples were removed from the moulds and carefully polished to obtain the correct height and parallel surfaces. The maximum compressive stress until failure was measured.

Shelf Life

2 ml syringes were filled with cement, the syringes were then sealed and stored in a desiccator at 5 and 21° C. Cement was extruded from the syringes every 3 days until the cement had become too hard to be extruded.

The results are set forth in Table 2:

TABLE 2 Results Cement 1 Cement 2 Property (MCPM + MCPA) (MCPA) Setting time 30-40 min 30-40 min Compressive strength 8-10 MPa 8-10 MPa Shelf life, 21° C. 9 days 27 days

Example 3

This example shows a number of formulations using MCPA with different particle sizes and powder to liquid ratios. The results show that a larger grain size of the MCPA provides means to control the setting time, injection force and strength of the hardened material.

Cement Preparation

The cement consisted of monocalcium phosphate anhydrous (MCPA) and β-tri calcium phosphate (β-TCP), in a molar ratio of 1:1. Glycerol (anhydrous) was used as mixing liquid. The MCPA was sieved in order to obtain the following particle sizes: <100 μm, 100-200 μm, 200-400 μm, and 400-600 μm. MCPA was also used as received, containing all the mentioned particle sizes, hereby referred to as ALL. A vacuum mixer was used to mix the cements. All evaluated cement mixtures are listed in the Table 3:

TABLE 3 Evaluated Cements Particle size (μm) P/L (g/ml) <100 3.9, 4.2 100-200 4.0, 4.2 200-400 4.2 400-600 4.2, 4.4 ALL 4.2

Injectability

The injectability was evaluated by measuring the force needed to inject 2 ml of cement paste from a disposable syringe; barrel diameter 8.55 mm, outlet diameter 1.90 mm. The force applied to the syringe during the injection was measured and mean injection force from 10 to 30 mm displacement was calculated, this force is referred to as the injection force.

Setting Time (ST)

To evaluate setting time, the cement was injected in four cylindrical moulds diameter 6 mm, height 3 mm. At t=0, the filled moulds were immersed in 37° C. phosphate buffered saline solution (PBS, pH 7.4, Sigma), to simulate in vivo conditions. The cement was considered to have set when the sample could support the 453.5 g Gillmore needle with a tip diameter of 1.06 mm without breaking.

Compressive Strength (CS)

For CS measurements, the paste was injected into cylindrical moulds and immersed in 50 ml PBS at 37° C. in a sealed beaker. Sample dimensions were diameter 6 mm and height 12 mm. After 24 h, the samples were removed from the moulds and carefully polished to obtain the correct height and parallel surfaces. The maximum compressive stress until failure was measured.

The results are set forth in Table 4:

TABLE 4 Results Grain size P/L Injection Setting time Compressive (μm) (g/mL) force (N) (min) strength (MPa) <100 3.9 120 ± 10 30-40 10-13 <100 4.2 240 ± 10 25-35 12-13 100-200 4.0 100 ± 10 30-40  9-12 100-200 4.2 180 ± 10 25-35 10-12 200-400 4.2 100 ± 10 25-35 7-9 400-600 4.2  90 ± 10 30-40 6-8 400-600 4.4 180 ± 10 25-35 7-9 ALL 4.2 110 ± 10 25-35  8-10

The specific examples and embodiments described herein are exemplary only in nature and are not intended to be limiting of the invention defined by the claims. Further embodiments and examples, and advantages thereof, will be apparent to one of ordinary skill in the art in view of this specification and are within the scope of the claimed invention. 

1. A non-aqueous hydraulic cement composition, comprising a non-aqueous mixture of (a) β-tricalcium phosphate powder, (b) monocalcium phosphate comprising monocalcium phosphate anhydrous (MCPA), monocalcium phosphate monohydrate (MCPM), or a combination thereof, and (c) non-aqueous water-miscible liquid, wherein a 0.1 g/ml saturated aqueous solution of the monocalcium phosphate has a pH less than 3.0.
 2. The non-aqueous hydraulic cement composition of claim 1, wherein a 0.1 g/ml saturated aqueous solution of the monocalcium phosphate has a pH less than 3.0 and greater than 2.0.
 3. The non-aqueous hydraulic cement composition of claim 1, wherein a 0.1 g/ml saturated aqueous solution of the monocalcium phosphate has a pH of about 2.5-2.8.
 4. The non-aqueous hydraulic cement composition of claim 1, wherein the monocalcium phosphate comprises monocalcium phosphate anhydrous (MCPA).
 5. The non-aqueous hydraulic cement composition of claim 4, wherein the monocalcium phosphate consists essentially of monocalcium phosphate anhydrous (MCPA).
 6. The non-aqueous hydraulic cement composition of claim 4, wherein at least 75% of the monocalcium phosphate has a particle size in a range of about 200-600 μm.
 7. The non-aqueous hydraulic cement composition of claim 6, wherein the composition has a powder (weight) to liquid (volume) ratio of about 2-5.
 8. The non-aqueous hydraulic cement composition of claim 4, wherein at least 75% of the monocalcium phosphate has a particle size in a range of about 1-100 μm.
 9. The non-aqueous hydraulic cement composition of claim 8, wherein the composition has a powder (weight) to liquid (volume) ratio of about 3-4.5.
 10. The non-aqueous hydraulic cement composition of claim 1, further comprising porous β-tricalcium phosphate granules.
 11. The non-aqueous hydraulic cement composition of claim 1, wherein the composition has a powder (weight) to liquid (volume) ratio of about 0.5-10.
 12. The non-aqueous hydraulic cement composition of claim 1, further comprising one or more of a surfactant, a porogen and a gelling agent.
 13. A method of preparing a hardened cement, comprising contacting the hydraulic cement composition of claim 1 with a hydrating liquid.
 14. The method of claim 13, wherein the hydrating liquid comprises water.
 15. A hardened cement formed according to the method of claim
 13. 16. The method of claim 13, wherein the non-aqueous hydraulic cement composition is injected in vivo and the hydrating liquid comprises a body fluid.
 17. An article of manufacture comprising a container filled with the non-aqueous hydraulic cement composition of claim
 1. 18. The article of manufacture of claim 17, wherein the container is a syringe.
 19. The article of manufacture of claim 17, wherein the container is a vacuum package.
 20. A kit comprising an article of manufacture according to claim 17 and a separately-contained quantity of hydrating liquid. 